The galvanization of β-amyloid in Alzheimer's disease

Whereas a decade ago thoughts of metals and Alzheimer's disease (AD) conjured up thoughts of tossing out your aluminum cookware, more recently, zinc, copper, and iron have been implicated in AD pathology. These metals are not derived from your saucepan or deodorant, but are already resident in the brain. Zinc is not a trace metal in the brain. In fact, zinc, copper, and iron concentrations in gray matter are in the same order of magnitude as magnesium (0.1–0.5 mM; refs. 1 and 2) and their participation in major neurological diseases is being increasingly appreciated (3). The argument for exploiting the interaction between β-amyloid (Aβ), and cortical zinc and copper, in designing novel therapies for AD has gathered considerable momentum over the last 5 years. This notion was originally prompted by the finding that the precipitation and redox activity of Aβ are modulated by copper, iron, and zinc (4–11). In this issue of PNAS, Lee et al. (12) report the marked decrease in Aβ deposition in the brains of Tg2576 mice lacking the synaptic ZnT3 zinc transporter. These findings provide in vivo evidence that the characteristic amyloid neuropathology of AD is principally caused by zinc released during neurotransmission. These data will likely have a significant impact on the development of drugs aimed at attenuating β-amyloid pathology underlying AD neurodegeneration (13). The zinc model for AD (Fig. 1) that emerges from these and other findings is more complex than the widely held Aβ autoaggregation model. However, it is also more satisfying because it can explain mysteries such as why Aβ deposits exclusively in the brain, why women more frequently develop Alzheimer's disease, and why rats and mice do not. Amyloid neuropathology of Alzheimer's disease is principally caused by zinc released during neurotransmission.